[The importance of toxicology for clinical pharmacology].
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Biomedical subjects
Publications and source records attributed to S Kaumeier.
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In an open study involving 30 schizophrenic patients the neuroleptic threshold dose (measured via Haase's graphopathological test), the maximum dose, and the maintenance dose were determined. The neuroleptic threshold dose was 5.6 mg/day (0.08 mg/kg body weight); the maximum dose was 11 mg/day (0.16 mg/kg body weight); and the maintenance dose was 6 mg/day (0.09 mg/kg body weight). With reference to the effectiveness, good to very good results were obtained in 19 cases. Regarding side effects 15 patients complained of extrapyramidal disturbances, this was to be expected in view of the study design aiming at the determination of the maximum dose level. When administered in one single dose in the evening, bromperidol influenced the night sleep positively, so that sleep-inducing drugs could be reduced, and, in some cases, even dispensed with.
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This contribution is concerned with a critical appraisal of the concept that plasma levels of psychotropic agents govern their pharmacodynamic action. In this regard, there are at least three problems: 1. identification of the chemical course of reaction between the introduced pharmacon and its resultant metabolites in reference to the totality of the organism and its biochemical reaction pattern; 2. the course of this reaction relative to intra- and interindividual differences; and 3. the influence of the kinetics as a result of concentration diversities, conditioned by different distributing patterns within the organism. Decisive factors here are: mode of application, blood distribution volume, reaction and/or elimination rate, and, finally, interaction of combined drugs.
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Infusions of large volumes have a remarkable influence on the blood levels of gentamycin insofar that with normal dosages no effective concentrations can be found in the serum of the patient. The present investigation was planned as a pharmacokinetic model with the aim of finding out the possible reasons for this phenomenon. The results show that the infusions enhance the total clearance tremendously. Furthermore the elimination half-life of gentamycin is much shorter under infusion conditions. This explains the subtherapeutic blood levels.
9,10-Dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol (danitracen, WA 335) is a substance with a stronger peripheral and partly central antiserotonin and antihistamine effect than cyproheptadine. In 5 different hospitals, WA 335 (3 X 1 mg/die) was investigated versus amitriptyline (3 X 50 mg/die) in a double-blind study in 116 depressive patients of different nosology. In the end of the investigation period (20 days), under WA 335 treatment 67.7% and under ami-riptyline treatment 66.7% of the patients showed an improvement of 50% = decrease in the Hamilton depression score. However, a decrease of 50% in the selfrating scale (von Zerssen) was only shown by 57% of the patients under WA 335 administration and 51% under amitriptyline administration. There were no significant differences seen as regards course and side effects of the two drugs. Like amitriptyline, WA 335 shows sedative properties at the beginning of therapy.
The metabolism of propafenone was studied in three humans by using 300 mg of the deuterated compound given orally. The excretion of propafenone and its metabolites was assessed by measuring the deuterium content in the excretion products by means of a microwave plasma detector. At selected times the metabolic pattern in plasma, urine, bile and feces was determined. The metabolites were isolated and the structure of the main compounds was characterized. Propafenone is absorbed completely and quantitatively metabolized. Unchanged propafenone is excreted neither in the urine nor in the feces in amounts of more than 1% the dose. The percentage of free unconjugated propafenone of the total deuterium content in the plasma was about 10% 3 and 6 hours after application. Conjugates of hydroxylated derivatives of propafenone are present predominantly in the plasma. The excretion of the metabolites takes place mainly by way of the feces, 53% of the dose is excreted by this route within 48 hours. Urinary elimination accounted for 18.5 and 38% of the dose within 48 hours in two humans. It was possible to elucidate the structure of 11 metabolites, accounting for more than 90% of the dose administered. The major metabolites are conjugates of 5-hydroxypropafenone and hydroxy-methoxy-propafenone with glucuronic and sulphuric acid and propafenone glucuronide. Furthermore, metabolic products of oxydative deamination pathway were identified, i.e. a glycol and a lactic acid derivative. C-C splitting yields a relatively large amount of 3-phenyl-propionic acid, while cleavage of the ether group leads to a phenolic product and is only of minor importance.
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The following statements can be made on the basis of our study. 1. The butyrophenone bromperidol is an absolutely effective drug of the series of very high-potency neuroleptics, with a mean neuroleptic threshold dose of 5.6 mg/day. The mean optimum dose is 6 mg/day, and the mean maximum dose reaches 11 mg/day, i.e. twice the neuroleptic threshold dose. 2. The substance is generally well tolerated; when it was administered to one third of all cases in one single dose in the evening, it not only had the same beneficial neuroleptic-antipsychotic effect as on administration t.i.d., but also positively influenced sleep, so that sleep-inducing drugs could be reduced and, in some cases, even dispensed with. This relatively long-lasting effect confirms the finding made in animal experiments.